1. Field of the Invention
The present invention is concerned with balancing the uricosuric and diuretic properties of indacrinone, a racemic compound, through manipulation of the proportion of its (+) and (-) enantiomers.
There continues to be a great deal of interest in the discovery and development of diuretics which are also uricosuric, since nearly all currently available diuretics commonly lead to urate retention, hyperuricemia, and, occasionally, attacks of gout. Hyperuricemia, in turn, may itself be a risk factor for the development of cardiovascular disease, carbohydrate intolerance, and urate-induced nephropathy. A large percentage of hypertensive patients have hyperuricemia.
For example, ticrynafen, or tienilic acid, produces a prompt diuresis with an increased excretion of sodium and chloride, while at maximal drug effect, uric acid clearance increases about five-fold. This drug was approved for use as an antihypertensive agent in the United States in 1979, but it was later withdrawn when postmarketing surveillance revealed an unacceptably high incidence of hepatotoxicity.
Uric acid transport by the renal tubules involves both readsorptive and secretory processes. There has been an interest in the mechanism of action of drugs that directly influence tubular transport systems for uric acid and thus alter the rate of uric acid excretion. Probenecid, for example, increases the urinary excretion of uric acid by inhibition of carrier-mediated reabsorption. Likewise, indacrinone or indacrynic acid, utilized in the present invention, inhibits urate reabsorption in the proximal tubule.
The action of uricosuric agents is often seemingly contradictory, because of the complexity of the transport mechanisms involved. Thus, increase, decrease, or lack of effect on the excretion of uric acid is not only highly species dependent, but dosage dependent as well. Moreover, depending on the exact conditions, the combined effect of two uricosuric drugs may be either additive or antagonistic.
The renal transport of uric acid in mammals involves both secretion and reabsorption, but in man the process of reabsorption dominates so that the amount that is excreted is but a small fraction of that which is filtered. A variety of factors, including uricosuric drugs, can influence the relative importance of these bidirectional transport mechanisms in man. Also, as already indicated above, uric acid is transported by carrier-mediated mechanisms and not by diffusion, and in man the site of transport is located in the proximal tubule, including both the convoluted and straight portions.
2. Brief Description of the Prior Art
Indacrinone, as a racemic mixture, and as the (+) or (-) enantiomer, is described in U.S. Pat. No. 4,096,267, which also refers generally to the possibility of combining different indanones disclosed where greater diuretic activity and greater uricosuric activity are possessed by said indanones. However, nothing in this reference would suggest manipulation of the proportion of (+) and (-) enantiomers of indacrinone within critical limits, for careful balancing of uricosuric and diuretic properties to give maximum therapeutic benefit, which has been accomplished with the present invention.
The different pharmacodynamic effects of the (+) and (-) enantiomers of indacrinone, specifically that the principal saluretic activity of indacrinone resides in the (-) enantiomer while uricosuric activity is present in both (-) and (+) enantiomers, are described by Irvin et al., Clin. Pharmacol. Ther., p. 260 (Feb. 1980); deSolms et al., J. Med. Chem., Vol. 21, No. 5, pp. 437-443 (1978); and Woltersdorf et al. ACS Symposium Series No. 83 Diuretic Agents, pp. 219-220 (1978). However, none of these publications in any way suggest manipulation of the proportion of (+) and (-) enantiomers of indacrinone within critical limits so as to achieve the maximum therapeutic benefit from balanced uricosuric and diuretic properties, as is the case with the present invention.
British Pat. No. 1,475,177 describes the combination of indacrinone racemic mixture, or the (-) enantiomer of indacrinone, with a potassium-sparing pyrazinoylguanidine diuretic, especially amiloride. However, this patent does not disclose or suggest a manipulated proportion of (+) and (-) enantiomers of indacrinone, or the combination of such a manipulated proportion with amiloride or other pyrazinoylguanidine diuretics.
U.S. Pat. No. 4,087,542 describes the diuretic (+) isomer and uricosuric (-) isomer of 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid and teaches manipulating the ratio of these isomers to achieve a balance of diuretic and uricosuric properties. However, there is a total separation of diuretic and uricosuric activity between the two isomers, and the manipulation of these isomers would not be instructive as to even the possibility of manipulating the (+) and (-) enantiomers of indacrinone, a wholly different compound. Furthermore, at present there is not known to be any marketed or experimental drug in which a ratio of enantiomers other than the synthetically occurring 50:50 is used.